History:

A 25 year old man has multiple, irregular lightly pigmented 1 to 5 cm macular (flat) skin lesions scattered on the skin of his trunk and extremities. He also has multiple firm 0.3 to 1 cm skin nodules that are not painful, but are disfiguring. He develops an S-shaped curvature to his spine. At age 25 he notes pain and swelling of his right wrist. An MRI scan of his right arm demonstrates a 3 cm mass lesion eroding the ulna.

Questions:

1. What inheritance pattern would you suspect in this case?

Genetic diseases that involve structure tend to be autosomal dominant.

2. Explain the absence of a family history for this disorder.

Spontaneous new mutations account for half of cases encountered (the overall incidence for NF-1 is 1 in 3000). This is often the case with autosomal dominant conditions.

3. What is the molecular basis for this disease?

Mutation of the NF1 gene on chromosome 17 causes von Recklinghausen's disease. The NF1 gene is a tumor suppressor gene; it encodes a protein, neurofibromin, which modulates signal transduction through the ras GTPase pathway.

The NF2 gene on chromosome 22q codes for a protein called neurofibromin 2, schwannomin, or merlin, with homology to a family of cytoskeletal proteins that includes moesin, ezrin, and radixin.

4. Name the lesions present.

The macules are cafe-au-lait spots. The skin nodules are neurofibromas.

5. What is the most likely diagnosis for the mass involving the right arm?

The larger erosive mass is a neurofibrosarcoma. Patients with NF1 are at increased risk of developing nervous system neoplasms, including plexiform neurofibromas, optic gliomas, ependymomas, meningiomas, astrocytomas, and pheochromocytomas. Neurofibromas may undergo secondary malignant degeneration and become sarcomas.

CNS tumors including schwannomas, meningiomas, and gliomas may occur with NF-2, which is much less common than NF-1.